IL-1alpha mediates cellular cross-talk in the airway epithelial mesenchymal trophic unit

Abstract

The bronchial epithelium and underlying fibroblasts form an epithelial mesenchymal trophic unit (EMTU) which controls the airway microenvironment. We hypothesised that cell-cell communication within the EMTU propagates and amplifies the innate immune response to respiratory viral infections.

EMTU co-culture models incorporating polarized (16HBE14o-) or differentiated primary human bronchial epithelial cells (HBECs) and fibroblasts were challenged with double-stranded RNA (dsRNA) or rhinovirus.

In the polarized EMTU model, dsRNA affected ionic but not macromolecular permeability or cell viability. Compared with epithelial monocultures, dsRNA-stimulated pro-inflammatory mediator release was synergistically enhanced in the basolateral compartment of the EMTU model, with the exception of IL-1alpha which was unaffected by the presence of fibroblasts. Blockade of IL-1 signalling with IL-1 receptor antagonist (IL-1Ra) completely abrogated dsRNA-induced basolateral release of mediators except CXCL10. Fibroblasts were the main responders to epithelial-derived IL-1 since exogenous IL-1alpha induced pro-inflammatory mediator release from fibroblast but not epithelial monocultures. Our findings were confirmed in a differentiated EMTU model where rhinovirus infection of primary HBECs and fibroblasts resulted in synergistic induction of basolateral IL-6 that was significantly abrogated by IL-1Ra. This study provides the first direct evidence of integrated IL-1 signalling within the EMTU to propagate inflammatory responses to viral infection.

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Identifiers

ORCID for Alison R. Hill: orcid.org/0000-0001-5397-873X

ORCID for Cornelia Blume: orcid.org/0000-0001-6133-7318

ORCID for Liku Tezera: orcid.org/0000-0002-7898-6709

ORCID for Donna E. Davies: orcid.org/0000-0002-5117-2991

ORCID for Emily J. Swindle: orcid.org/0000-0003-3644-7747

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